Partial MHC/neuroantigen peptide constructs attenuate methamphetamine-seeking and brain chemokine (C–C motif) ligand 2 levels in rats

Abstract

There are no medications that target the neurotoxic effects or reduce the use of methamphetamine. Recombinant T-cell receptor ligand (RTL) 1000 [a partial major histocompatibility complex (pMHC) class II construct with a tethered myelin peptide], addresses the neuroimmune effects of methamphetamine addiction by competitively inhibiting the disease-promoting activity of macrophage migration inhibitory factor to CD74, a key pathway involved in several chronic inflammatory conditions, including substance use disorders. We previously reported that RTL constructs improve learning and memory impairments and central nervous system (CNS) inflammation induced by methamphetamine in mouse models. The present study in Lewis rats evaluated the effects of RTL1000 on maintenance of self-administration and cue-induced reinstatement using operant behavioral methods. Post-mortem brain and serum samples were evaluated for the levels of inflammatory factors. Rats treated with RTL1000 displayed significantly fewer presses on the active lever as compared to rats treated with vehicle during the initial extinction session, indicating more rapid extinction in the presence of RTL1000. Immunoblotting of rat brain sections revealed reduced levels of the pro-inflammatory chemokine (C–C motif) ligand 2 (CCL2) in the frontal cortex of rats treated with RTL1000, as compared to vehicle. Post hoc analysis identified a positive association between the levels of CCL2 detected in the frontal cortex and the number of lever presses during the first extinction session. Taken together, results suggest that RTL1000 may block downstream inflammatory effects of methamphetamine exposure and facilitate reduced drug seeking—potentially offering a new strategy for the treatment of methamphetamine-induced CNS injury and neuropsychiatric impairments.